Targeting Mas Receptor for Diabetic Vascular Disease in Older Adults Abstract Prevalence of diabetes is high among older adults and is expected to rise, and diabetes increases risk for cardiovascular disease. Accumulated evidence suggests that bone marrow-derived progenitor cells maintain vascular health and promote rapid repair following vascular injury. This innate vascular protection is diminished with aging and diabetes due to impaired mobilization of EPCs from bone marrow into circulation and decreased ability to repair damaged blood vessels. Therefore approaches that preserve EPC mobilization and function will prevent the development of vascular disease in older adults with diabetes. We hypothesize that the Mas receptor, the functional mediator of the vasoprotective axis of renin angiotensin system, confers mobilization and reparative functions in EPCs and that early intervention with MasR activation would preserve innate vasoprotection and prevents the development of vascular disease with aging and diabetes. This hypothesis is based on our novel findings that showed angiotensin converting enzyme-2 that generates heptapeptide angiotensin (Ang)-(1-7), the endogenous activator of MasR, is down-regulated with aging and diabetes. Importantly, genetic deficiency of MasR (MasR-KO) precipitates EPC moblilopathy and vasoreparative dysfunction following ischemic vascular injury, similar to aging and diabetes. Three aims are proposed to test the hypothesis. Aim-1 will define the role of MasR in the mobilization and vasoreparative functions of EPCs by using radiation chimeras of MasR-KO mice. Aim-2 will test the beneficial effects of long- term activation of MasR on the development of vasoreparative dysfunction with aging and diabetes. This will be accomplished by overexpressing Ang-(1-7) by adenoviral or nonviral approaches. We will test if the overexpression of Ang-(1-7) will reverse the vasoreparative dysfunction in CD34+EPCs derived from older adults with diabetes. Therefore Aim-2 will provide the proof-of-concept for the translational potential of the study. Aim 3 will demonstrate the involvement of novel pathways that mediate the reversal of mobilization and vasoreparative dysfunctions in diabetic EPCs by MasR activation, Slit/Robo/ROCK pathway and TERT/mitoROS/NO pathway, respectively. Overall, this study will provide a novel mechanism-based pharmacological approach for reversal as well as prevention of diabetic vascular disease in older adults with diabetes.